Project Summary Dr. Reilly has a track record in unique mechanistic patient oriented research (POR) and mentorship at the University of Pennsylvania (Penn). His Cardiometabolic Research Program is dedicated to human translational and genomic studies of atherosclerotic cardiovascular disease (ASCVD) and its risk factors. His program is based in Penn's Cardiovascular and Translational Institutes and highly integrated into the training missions sponsored by Penn's Clinical and Translational Science Award. This provides an outstanding environment for translational POR and for mentoring K24 trainees. He has had a track record of continuous NIH funding, mentorship of multiple physician scientists in translational POR, and numerous high-impact translational publications led by over a dozen trainees, several of whom have established their own independent POR careers. Dr Reilly recognizes the challenges to incorporating basic science and cutting edge translational technologies into academic careers in POR. He is committed to training young clinical investigators in these approaches and mentoring them to independent careers in POR. In this application, he proposes to (1) augment his scientific and mentoring skills and devote more time to mechanistic POR, (2) provide increased time and structure in mentoring new clinical investigators in the conduct of mechanistic POR, and (3) pursue new innovative POR in order to provide a unique training environment and POR framework for mentoring young clinical investigators. Although recent genomic discoveries have identified novel associations with ASCVD and its risk factors, the key challenge remains in demonstrating how these loci cause disease and can be advanced for clinical application and therapeutic targeting. The proposed K24 research will recruit healthy humans to generate induced pluripotent stem (iPS) cells from adipose tissue biopsies. The iPS cells will be used to address pilot studies tissue-specific functional studies of recent genomic discoveries for heart disease, (a) SORT1, a novel LDL-cholesterol and myocardial infarction locus, in regulation of hepatocyte lipoproteins and, (b) ABO, a locus for risk endothelial risk biomarkers and myocardial infarction, in regulation of endothelial secreted proteins. Dr Reilly will dedicate 40% effort to this K24 proposal (5% to augment his mentorship and POR skills; 10% to the research proposal; and 25% to mentoring new investigators) through reduction in administrative and clinical duties. The K24 award provides the ideal mechanism to expand his mechanistic POR program while simultaneously dedicating significant effort to train young clinical investigators.